Differential control of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases.
Differential control of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases.
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DOI：
10.1074/jbc.m117.805424
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发表时间：
2018-02-16
期刊：
影响因子：
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通讯作者：
Arthur JSC
中科院分区：
文献类型：
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作者：
Sutavani RV;Phair IR;Barker R;McFarlane A;Shpiro N;Lang S;Woodland A;Arthur JSC
越来越多的证据表明，IL-10+ve B细胞产生的白细胞介素（IL）-10失调与自身免疫有关，这凸显了提高对这些细胞中IL-10产生调节的理解的重要性。在B细胞和骨髓细胞中，IL-10可以响应于Toll样受体（TLR）激动剂而产生。在巨噬细胞中，先前的研究已经确定，丝裂原和应激活化蛋白激酶（MSK）通过IL-10启动子上的cAMP反应元件结合（CREB）蛋白的磷酸化来调节IL-10的产生。我们发现，尽管在腹膜B细胞中，MSKs响应于TLR 4激动剂而被激活，但在这些细胞中，IL-10的产生既不需要MSKs也不需要CREB。使用化学抑制剂和基因敲除小鼠的组合，我们发现B细胞中的IL-10诱导受ERK 1/2和p90核糖体S6激酶依赖性机制的调节，不像巨噬细胞中不需要p90核糖体S6激酶。这一观察结果突出了控制B细胞和巨噬细胞中IL-10产生的信号传导的根本差异，即使这两种细胞类型响应于共同的TLR刺激。
Increasing evidence has linked dysregulated interleukin (IL)-10 production by IL-10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element–binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinase-dependent mechanism, unlike in macrophages in which p90 ribosomal S6 kinase was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus.